Functional Dyspepsia

Michael Fried Division of Gastroenterology and Hepatology

University Hospital Zurich, Switzerland

Dyspepsia

Functional Dyspepsia

Non-GI Causes (cardiac disease,

muscular pain, etc.)

Structural Dyspepsia (GERD, PUD, pancreatic disease, gallstones, etc.)

Diagnostic Criteria* for Functional Dyspepsia

Rome III

* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.

Must include one or more of the following:

and no evidence of structural disease (including upper endoscopy) to explain the symptoms

Bothersome postprandial

fullness

Early satiation

Epigastric pain

Epigastric burning or or or

Tack J et al, Gastroenterology, 2006;130:1466–1479

Pathophysiology ?

Carbone F and Tack J. Dig Dis 2014, 32: 222-229

Futagami S et al. Aliment Pharmacol Ther 2015; 41: 177-188

Post‐infectious FD and IBS

Do subtypes make sense?

• 27% non-specific

• 31% overlapping

Talley et al. 2001. J Clin Gastroenterol Talley et al. Gastroenterology 1993

Bytzer et al. Scand J Gastroenterology 1992

Lack of discriminant value of dyspepsia subgroups

Dyspepsia: a symptom complex

< 0.1% 1 symptom; 99% >2 symptoms; > 80% >5

Tack J et al, Gastroenterology, 2006;130:1466–1479

Ford AC et al. Clin Gastroenterol Hepatol. 2010; 8: 830-837

Meta-analysis, 151 papers included, N= 5389 patients

Broad definition of dyspepsia

Rome 3 criteria for dyspepsia

DD

Main differential diagnoses for dyspepsia 1. Peptic ulcer (chronic) 2. GERD (w/wo esophagitis) 3. Malignant disease 4. Functional dyspepsia

Diagnosis after exclusion

AGA Technical Review on the Evaluation of Functional Dyspepsia. Gastroenterology 2005

Organic causes of dyspeptic symptoms

• Peptic clcer disease • GERD • Medications (ASA/NSAIDS, Abx) • Gastroparesis • Gastric neoplasm • Cholelithiasis, choledocholithiasis • Pancreatitis (acute or chronic) • Carbohydrate malabsorption • Ischemic bowel disease • Other GI malignancy (ep. Pancreatic cancer) • Systemic disease (DM, Thyroid, Parathyroid, CTD) • Intestinal parasites

Medications and dyspepsia

• NSAR cause dyspepsia in up to 20% of the patients (including COX-2 inhibitors)

• COX-2 inhibitor consumation decreases, but low dose aspirin use increases

• Identify: - Alendronat - Acarbose - Metformin - Orlistat - Digitalis - Theophylline - Potassium - Antibiotics (Erythromycin)

Hawkey et al. Gut 2003

Bytzer et Hallas. Aliment Pharmacol Ther 2000 Ofman et al. Arthritis Rheum 2003

Overland MK. Med Clin N Am; 2014; 98: 549-564

Etiology of dyspepsic symptoms ?

Alarm symptoms and signs History • Weight loss

• Dysphagia

• Recurrent vomiting

• Icterus

• FA: Ca / Celiac d.

• Onset > 45 yrs

Signs

• Fever

• Pathological status

• GI bleeding signs

Lab

• Anemia, Fe-deficiency

• Leukocytosis

• CRP

Wallace MB et al. Gut 2001; 49: 29-34

Age > 45 or any alarm symptom as predictor of major endoscopic findings

• Canadian trial (7004 pts <45 years, dyspepsia, no alarm symptoms)

− 7% «significant» diagnoses – 31% normal – 30% gastritis – 23% reflux esophagitis

• Asian trial (387 pts, 45 years years, dyspepsia, no alarm symptoms)

− higher patients satisfaction by endoscopy (40 % vs 22 %)

• Danish trial (FD pts, 317 completed) − reassurance by endoscopy − cost-effective (but PPI at that time expensive)

Breslin et al. Gut 2000. 46:93-7 Mahadeva: Gut 2008. 57: 1214-20

Bytzer et al. Lancet 1994. 343:811-16

To scope or not? Benefit of upper gi endoscopy

Abdominal sonography ?

• explains only rarely patients symptoms

• therapeutic gain only 1-3%

- exclusion of pancreas pathology

- gallbladder stones mostly incidental

• not recommended in patients < 45 years

AGA Technical Review: Gastroenterology 2005; 129:1756-80

DGVS-Leitlinien – Z Gastroenterol 2001; 39:937-956

General therapeutic measures in FD ?

• Explanation of benign nature of disease ("re-assurance")

• Good patient-doctor relationship

• Dietary counceling (diet assessment, more meals, smaller portions, less fat, avoidance of nutrients which induce symptoms)

• Healthy life style

Talley et al. Am J Gastroenterol 2005 Lacy et al. AP&T 2012

Functional dyspepsia – always PPI ?

41 % (PPI) vs. 32 % (placebo) RR- reduction 10 % (95% CI, 2.7%– 17.3%) NNT 14

Wang WH et al. Clin Gastroenterol Hepatol 2007;5:178-85

Favors PPI Favors plac.

Metaanalysis (2007), 3725 patients

• PPI effective in patients with EPS and refluxlike symptoms, less effective in patients with PDS-type dyspepsia • Lower dose equivalent to standard dose (e.g.: 10 mg vs. 20 mg omeprazole)

PPI • Basic therapy • Effect independent of dose • More effective in EPS with refluxlike symptoms

• Newer data

– Japan: PPI monotherapy better than H2-RA + prokinetic for PDS – China: PPI more effective for treatment of epigastric burning than

pain, postprandial fullness, early satiety

Sakaguchi et al. World J Gastroenterol. 2012; 18: 1517-24 Xiao et al. Am J Gastroenterol 2010;105: 2026-31

Symptom improvement after HP -Eradication?

• metaanalysis (Cochrane database) 2006, 21 RCT / 3566 pts.

• H. pylori eradication has a small (but significant) effect in H.pylori positive functional dyspepsia

• NNT = 15

Suzuki et al, J Neurogastroenterol Motil 2011; 17 Moayyedi P et al. Cochrane Database Syst Rev 2006

Antidepressants for functional dyspepsia ?

12 heterogenous small studies: relative risk reduction 45% vs placebo

2/4 studies with levosulpiride

Hojo M et al. J Gastroenterol 2005;40:1036-42

Antidepressants

• Amitryptiline (Saroten®; 3x10mg/d) • Japanese RCT, 27 FD patients with no response to H2-RA/prokinetics

Otaka M et al. APT 2006; 21S:42-46

Hypnotherapy ?

Calvert EL et al. Gastroenterol 2002;123:1778-85

126 patients randomized to • hypnotherapy (3 not completed) • supportive therapy (13 not completed) • conventional treatment (10 not completed)

Functional dyspepsia – prokinetics ?

Hiyama T et al. J Gastroenterol Hepatol 2007;22: 304-10

Metaanalysis 2007, 27 studies: relative risk reduction (symptom free): 33% with prokinetic vs. plac NNT=6 BUT: • no longterm data • 21/27 studies with cisapride (unavailable) • domperidon (Motilium®) and metoclopramide (Paspertin®): less

effective than cisapride

Veldhuyzen, van Zanten, Am J Gastroenterol 2001; 96: 689-696

Prokinetics: Levosulpiride (Dogmatil®)

Mearin F et al. Clin Gastroenterol Hepatol 2004.2: 301-308 Corazza GR, Biagi F, Albano O, et al. It J Gastroenterol 1996; 28: 317-323

Mansi C et al. Aliment Pharmacol Ther. 2000;14:56156-9

• Action − peripheral and central D2-receptor antagonist, partial ENS 5-HT4

agonist • Effects − more potent than domperidone, metoclopramide and cisparide to

reduce FD symptoms − similar efficacy to accelerate gastric emptying as cisapride

• Dose − 3x25mg - 3x50mg/d (Sanofi-Aventis, 50mg capsules) • Side effects − gastrointestinal, tachykardia, prolactin elevation

Lacy BE et al. Aliment Pharmacol Ther. 2012; 36: 3-15

Zala A et al. Expert Opin Emerging Drugs 2015; 20:221-233

• FD: disturbed motility, sensitivity, inflammation, brain factors • GI infections are risk factors for FD • Low predictive value of FD symptoms for a positive diagnosis • Alarm symptoms do not reliably predict organic disease • Patients with FD should at least have once a gastroscopy;

value of ultrasound is uncertain • PPIs are basic FD therapy, independent if patients present

reflux-like symptoms or not • HP eradication is effective in a small subgroup • Some (amitryptiline) antidepressants are effective to treat FD • Hypnotherapy has a long-term effect on FD symptoms • Prokinetics (sulpiride; acotiamide) should be tried if PPI, HP

eradication and antidepressants have failed

Take home messages

Pierre-Auguste Renoir. Le déjeuner des canotiers